PSD-95 PROTEIN FAMILY IN RECEPTOR CLUSTERING

描述：申请者的长期目标是了解分子 ASIS 具有突触功能。由于癫痫等许多神经系统疾病， 精神分裂症和抑郁症是由突触功能障碍引起的， E 在分子水平上对突触机制的理解应该提供 洞察这类疾病的基础。 从突触前终末释放的神经递质与特定的 打开位于突触后膜上的特定通道的受体 。 包括Recept在内的重要突触成分是如何形成的一直是个谜。 S 而通道则定位于突触膜的特定位置。一个 被称为突触后密度的特化的细胞骨架结构 与受体/通道定位的机制有关。应用程序 已经分离出编码PSD-95的基因，PSD-95是突触后的一种重要蛋白质 密度。最近，越来越多的证据表明，PSD-95蛋白是CRU 阿尔 一些受体和通道在SY的不同部位的定位 PTIC 膜，而定位过程是通过相互作用介导的 PSD-95和受体/通道蛋白的特定结构域。 该建议是为了研究PSD-95及其同系物在 受体/通道定位。这些高贵的PSD-95同系物有组织 与PSD-95不同的特异性，表明类似PSD-95的家族 蛋白质可能与组织特有的蛋白质相互作用。具体目标是 S 研究结果如下：(1)这些基因的mRNA和蛋白产物的组织定位 将通过原位杂交和免疫细胞化学进行检测，(2)Th GLGF PSD-95的结构域在与PSD-95的相互作用中起重要作用 受体/通道蛋白。将产生转基因小鼠来测试 这个 PSD-95的GLGF结构域过表达可能抑制受体聚集I 体内，(3)PSD-95的SH3结构域可能与一组不同的Pro相互作用 移民局， 但这种可能性尚未得到检验。他们将使用酵母双杂交 系统搜索这样的蛋白质，(4)GABAAβ受体亚单位组成 一个 与PSD-95相互作用所需的共识序列。这将是一场 泰德 这个亚基是否也可以被PSD-95蛋白聚集。

DESCRIPTION: The applicant's long term goal is to understand the molecular asis of synaptic function. Since many neurological diseases such as epilepsy, schizophrenia and depression, are caused by malfunctioning of the synapse, e understanding of synaptic mechanisms at the molecular level should provide insight into the basis of such diseases. Neurotransmitters released from the presynaptic terminals bind to specific receptors to open up specific channels localized on the postsynaptic membra . It has been a puzzle how the important synaptic components including recept s and channels become localized to specific sites of synaptic membranes. A specialized, cytoskeletal structure called postsynaptic density has been implicated in the mechanism of receptor/channel localization. The applican have isolated a gene encoding PSD-95, a prominent protein in the postsynapt density. Recently, evidence is accumulating that the PSD-95 protein is cru al for the localization of some receptors and channels at discrete sites of sy ptic membrane, and the localization process is mediated by interactions between specific domains of PSD-95 and receptor/channel proteins. The proposal is to study the roles of PSD-95 and its homologs in the receptor/channel localization. These noble PSD-95 homologs have tissue specificity distinct from PSD-95, suggesting that a family of PSD-95-like proteins may interact with tissue-specific proteins. The specific aims are s follows: (1) Tissue localization of mRNA and protein products of these gen will be examined by in situ hybridizations and immunocytochemistry, (2) Th GLGF domain of PSD-95 was shown to be important for the interaction with receptor/channel proteins. Transgenic mice will be generated to test wheth the overexpression of GLGF domain of PSD-95 might inhibit receptor clustering i vivo, (3) The SH3 domain of PSD-95 may interact with a different set of pro ins, but this possibility has not been tested. They will use a yeast two-hybrid system to search for such proteins, (4) GABAA beta receptor subunits contai a consensus sequence necessary for the interaction with PSD-95. It will be t ted whether this subunit can also be clustered by the PSD-95 protein.